The resumption of normal cell growth properties after re-establishment of gap junctional communication in tumor cells, has led to the idea that the gap junction proteins, connexins, act as tumor suppressors. However, the mechanisms by which connexins regulate cell growth are only beginning to be understood. Loss of gap junctional communication and changes in autocrine IGF-I signaling in breast cancer suggest that these two phenomena may be linked and that regulation of IGF-I signaling may be one mechanism of connexin43 (Cx43) tumor suppression in cancer. The research described in this proposal will examine the relationship between IGF-I signaling and Cx43 gap junctional communication using breast cancer cells as a model. The goal of Specific Aim 1 is to determine the effect of Cx43 re-expression on cell growth, differentiation and apoptosis in MCF-7 cells. The goal of Specific Aim 2 is to examine the effect of IGFIR activation on gap junctional communication. The goal of Specific Aim 3 is to determine the effect of Cx43 re-expression on secretion of insulin-like growth factor binding proteins (IGFBPs). Studying the effect of IGFIR activation on Cx43 as well as the effect of Cx43 on breast cancer cell growth and IGFBP secretion will provide novel insight into the role of intercellular communication in autocrine IGF-I signaling and potentially, demonstrate novel targets for chemotherapeutic intervention.